There is an unmet need for therapeutic drugs that restore cognitive function in people with intellectual disabilities. Fragile X syndrome (FXS) is th most frequent form of inherited intellectual disability. Currently available pharmacological intervention strategies for FXS primarily treat behavioral problems. A major challenge for FXS research is to develop treatment strategies that improve the intellectual capabilities of patients. The long-term goal is to better understand the molecular mechanisms and the neuroanatomical locus of cognitive impairments in FXS, and to identify disease mechanism-targeted treatment strategies that improve cognitive function in patients with FXS. The immediate objectives of this proposal are (1) to develop and test new pre-clinical tools to assess cognitive function in FXS by identifying higher-order cognitive deficiencies in a novel prefrontal cortex-selective FXS mouse model and (2) to test the phosphoinositide-3 kinase (PI3K) catalytic subunit p110 as a treatment target to correct molecular, cellular, behavioral, and, particularly, higher-order cognitive deficits in FXS. The rationale for the proposed work is twofold. Firstly, a major obstacl for many groups to identify drug targets improving intellectual capabilities is the lack of access to suitable assays of higher-order cognitive function in mice, a widely used model system for FXS. The present proposal will overcome this roadblock by identifying and correcting higher-order cognitive defects using a specialized experimental approach that directly tests complex cognition in FXS mouse models. Secondly, previous work strongly suggests that PI3K signaling is increased and dysregulated in FXS, which is caused, at least partially, by loss of translational regulation of the PI3K catalytic subunit p110. This justifies the hypothesis that pharmacological inhibition of p110 rescues molecular, cellular, behavioral and cognitive phenotypes of FXS. Notably, p110-selective inhibitors are currently used in clinical cancer trials, making p110 an especially promising drug target in FXS with potentially quick application in humans. Supported by strong preliminary data, the hypothesis will be tested by three aims. Under aim 1, a novel FXS mouse model will be developed using virus-mediated gene-silencing of Fmr1 in the prefrontal cortex, a brain region crucial for higher cognition and autism. A quantifiable defect in goal-directed decision-making in these and in Fmr1 KO mice will be identified. Aims 2 and 3 will test if a p110-selective inhibitor currently used in clinical trials with cancer patients, rescues molecular and cellular defects, and improves autistic-like behavior and cognition in the two FXS mouse models. This research is significant and innovative, because it will provide unique insight into the neuroanatomical etiology of cognitive dysfunction in FXS. It will, for the first time, pre clinically assess a therapeutic drug to improve the entire spectrum of FXS phenotypes, including higher cognition. It will take advantage of the 'head start' in cancer research by repurposing a p110-selective antagonist developed for use in cancer patients, to treat FXS. This approach will overcome limitations of previous pre-clinical studies in FXS and accelerate the identification of more efficient therapies.